U.S. patent application number 11/891674 was filed with the patent office on 2008-03-20 for device for treatment of disorders in the oral cavity with nitric oxide, and manufacturing process for the same.
Invention is credited to Tor Peters.
Application Number | 20080069863 11/891674 |
Document ID | / |
Family ID | 34933708 |
Filed Date | 2008-03-20 |
United States Patent
Application |
20080069863 |
Kind Code |
A1 |
Peters; Tor |
March 20, 2008 |
Device for treatment of disorders in the oral cavity with nitric
oxide, and manufacturing process for the same
Abstract
A device and method for therapeutical treatment of disorders in
the oral cavity and a process for manufacturing of said device is
disclosed. The device comprises a nitric oxide (NO) eluting
polymer. The nitric oxide (NO) eluting polymer is configured to
elute a therapeutic dosage of nitric oxide (NO) when used in the
oral cavity. The device allows for target treatment of infections
or wounds in the oral cavity. The device comprising the nitric
oxide (NO) eluting polymer is arranged to contact an infected area
in the oral cavity, such that a therapeutic dose of nitric oxide is
eluted from said nitric oxide eluting polymer to said area. The
nitric oxide (NO) eluting polymer is integrated with a carrier
material, such that said carrier material, in use, regulates and
controls the elution of said therapeutic dosage of nitric oxide
(NO).
Inventors: |
Peters; Tor; (Helsingborg,
SE) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
34933708 |
Appl. No.: |
11/891674 |
Filed: |
August 10, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/EP06/50888 |
Feb 13, 2006 |
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11891674 |
Aug 10, 2007 |
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60652758 |
Feb 14, 2005 |
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Current U.S.
Class: |
424/443 ;
424/489; 424/718 |
Current CPC
Class: |
A61K 9/7023 20130101;
A61K 8/84 20130101; A61K 8/046 20130101; A61C 19/063 20130101; A61K
8/72 20130101; A61P 43/00 20180101; A61Q 11/00 20130101; A61K 33/00
20130101; A61P 17/02 20180101; A61L 29/08 20130101; A61K 8/19
20130101; A61L 2300/114 20130101; A61L 29/048 20130101; A61P 31/04
20180101; A61L 29/16 20130101; A61P 1/02 20180101; A61P 35/00
20180101; A61K 9/006 20130101 |
Class at
Publication: |
424/443 ;
424/489; 424/718 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 33/00 20060101 A61K033/00; A61P 35/00 20060101
A61P035/00; A61P 43/00 20060101 A61P043/00; A61K 9/14 20060101
A61K009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 11, 2005 |
EP |
05002937.0 |
Claims
1. A non-implantable device configured to topically therapeutically
treat and/or prevent disorders in the oral cavity, wherein said
device comprises a nitric oxide (NO) eluting polymer configured to
elute a therapeutic dosage of nitric oxide (NO) when used for said
treatment and/or prevention of a target site in the oral cavity,
and wherein said device is configured for exposure of said target
site to said nitric oxide when said polymer elutes nitric oxide
(NO), and wherein said nitric oxide (NO) eluting polymer is
integrated with a carrier material, wherein said carrier material
regulates the elution of said therapeutic dosage of nitric oxide
(NO), wherein said device is a pad/patch, a condom/sheath, a
soluble film, a sponge, a cream, or a gel, and is adapted to be
applied to the oral cavity, wherein said device is activatable
immediately prior to introduction into said oral cavity or in said
oral cavity for release of said nitric oxide (NO) from said nitric
oxide (NO) eluting polymer, and independent of humidity in said
oral cavity, by a proton donor provided separately from said nitric
oxide (NO) eluting polymer.
2. The device according to claim 1, wherein said elution of nitric
oxide (NO) from said device is substantially directed towards said
target site for said exposure.
3. The device according to claim 1, further comprising a first
membrane, which is permeable to nitric oxide on a first side of the
device, wherein said first side is oriented towards said treatment
site, and a second membrane which has low permeability or
substantially no permeability to nitric oxide on a second side of
said device, wherein said second side is oriented away from said
treatment site, such that said substantial direction of nitric
oxide (NO) from said device is provided as the elution of nitric
oxide from said device and is substantially prevented from said
second side.
4. The device according to claim 1, wherein said nitric oxide (NO)
eluting polymer comprises diazeniumdiolate groups, S-nitrosylated
groups, O-nitrosylated groups, or any combination thereof.
5. The device according to claim 1, wherein said nitric oxide (NO)
eluting polymer is L-PEI (linear polyethyleneimine).
6. The device according to claim 1, wherein said nitric oxide
eluting polymer is selected from the group consisting of amino
cellulose, amino dextrans, chitosan, aminated chitosan,
polyethyleneimine, PEI-cellulose, polypropyleneimine,
polybutyleneimine, polyurethane, poly(buthanediol spermate),
poly(iminocarbonate), polypeptide, Carboxy Methyl Cellulose (CMC),
polystyrene, poly(vinyl chloride), and polydimethylsiloxane, and
any combination thereof, wherein said polymer is grafted to an
inert backbone selected from the group consisting of a
polysaccharide backbone and a cellulosic backbone.
7. The device according to claim 1, wherein said device is
configured to disintegrate in the oral cavity when subjected to
moisture or water.
8. The device according to claim 1, wherein said NO-eluting polymer
is combined with silver.
9. The device according to claim 1, wherein said carrier material
is selected from the group consisting of polyethylene,
polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates,
polylacticacids, starch, cellulose, polyhydroxyalkanoates,
polyesters, polycaprolactone, polyvinylalcohol, polystyrene,
polyethers, polycarbonates, polyamides, polyolefins, poly(acrylic
acid), Carboxy Methyl Cellulose (CMC), protein based polymers,
gelatine, biodegradable polymers, cotton, latex, and any
combination thereof.
10. The device according to claim 1, wherein said nitric oxide
eluting polymer is in the form of nanoparticles or
microspheres.
11. The device according to claim 10, wherein said nanoparticles or
microspheres are encapsulated in a material selected from the group
consisting of polyethylene, polypropylene, polyacrylonitrile,
polyurethane, polyvinylacetates, polylacticacids, starch,
cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone,
polyvinylalcohol, polystyrene, polyethers, polycarbonates,
polyamides, polyolefins, poly(acrylic acid), Carboxy Methyl
Cellulose (CMC), protein based polymers, gelatine, biodegradable
polymers, cotton, latex, and any combination thereof.
12. The device according to claim 10, wherein said nanoparticles or
microspheres are integrated into a toothpaste.
13. The device according to claim 1, wherein said nitric oxide
eluting polymer comprises a secondary amine in the backbone or a
secondary pendant amine.
14. The device according to claim 13, wherein a positive ligand is
located on a neighbor atom to the secondary amine.
15. The device according to claim 1, further comprising an
absorbent agent.
16. The device according to claim 15, wherein said absorbent agent
is selected from the group consisting of polyacrylate, polyethylene
oxide, Carboxy Methyl Cellulose (CMC), microcrystalline cellulose,
cotton, starch, and any combination thereof.
17. The device according to claim 1, further comprising a cation,
wherein said cation stabilizes the nitric oxide eluting
polymer.
18. The device according to claim 17, wherein said cation is
selected from the group consisting of Na.sup.+, K.sup.+, Li.sup.+,
Be.sup.2+, Ca.sup.2+, Mg.sup.2+, Ba.sup.2+, Sr.sup.2+, and any
combination thereof.
19. The device according to claim 1, wherein the nitric oxide
eluting polymer is in the form of a powder, nanoparticles or
microspheres, which is incorporated into a foam.
20. The device according to claim 19, wherein the foam has an open
cell structure configured to facilitate transport of said proton
donor to the nitric oxide eluting polymer.
21. The device according to claim 20, wherein the foam comprises a
polymer selected from the group consisting of polyethylene,
polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates,
polylacticacids, starch, cellulose, polyhydroxyalkanoates,
polyesters, polycaprolactone, polyvinylalcohol, polystyrene,
polyethers, polycarbonates, polyamides, polyolefins, poly(acrylic
acid), Carboxy Methyl Cellulose (CMC), protein based polymers,
gelatine, biodegradable polymers, cotton, latex and any combination
thereof.
22. The device according to claim 1, wherein the device is a
syringe-type device having two separate containers, wherein a first
container contains a proton donor-based NO release activation
agent, and a second container contains a non proton donor-based
gel, comprising the nitric oxide eluting polymer, wherein the
syringe-type device is configured to provide admixing upon
administration.
23. The device according to claim 1, wherein the device is further
activatable in said oral cavity for release of said nitric oxide
(NO) from said nitric oxide (NO) eluting polymer by humidity in
said oral cavity.
24. A manufacturing process for a device configured to
therapeutically treat and/or prevent disorders in the oral cavity
according to claim 1, comprising: selecting a nitric oxide (NO)
eluting polymer configured to elute a therapeutic dosage of nitric
oxide (NO) in the oral cavity when used for said therapeutic
treatment and/or prevention; selecting a carrier material
configured to regulate the elution of said therapeutic dosage of
nitric oxide (NO); incorporating the NO-eluting polymer with said
carrier material into an nitric oxide (NO) eluting material,
wherein said carrier material regulates the elution of said
therapeutic dosage of nitric oxide (NO); and deploying said nitric
oxide eluting material to form at least a part of said device, such
that said device is configured to expose a therapeutic target site
in the oral cavity to said nitric oxide when said NO-eluting
polymer elutes nitric oxide (NO); and providing said device as a
pad/patch, a condom/sheath, a soluble film, a sponge, a cream, or a
gel, wherein said device is adapted to be applied in the oral
cavity, wherein said device is activatable immediately prior to an
introduction into said oral cavity, or in said oral cavity, for
release of said nitric oxide (NO) from said nitric oxide (NO)
eluting polymer, and independent of humidity in said oral cavity,
by a proton donor provided separately from said nitric oxide (NO)
eluting polymer.
25. The manufacturing process according to claim 24, further
comprising applying a material that has low permeability or
substantially no permeability to nitric oxide (NO) on a side of
device that is intended to be oriented away from said therapeutic
target site, wherein elution of nitric oxide is substantially
directed towards said therapeutic target site.
26. The manufacturing process according to claim 24, wherein said
deploying comprises electro spinning, air spinning, gas spinning,
wet spinning, dry spinning, melt spinning, or gel spinning of said
NO-eluting polymer.
27. The manufacturing process according to claim 24, wherein said
selecting said nitric oxide (NO) eluting polymer comprises
selecting a plurality of nitric oxide (NO) eluting polymeric
particles selected from the group consisting of nanofibers,
nanoparticles and microspheres.
28. The manufacturing process according to claim 24, wherein said
incorporating said NO-eluting polymer with said carrier material
comprises integrating said NO-eluting polymer in said carrier
material, spinning said NO-eluting polymer together with said
carrier material, or spinning said NO-eluting polymer on top of
said carrier material.
29. The manufacturing process according to claim 24, further
comprising integrating silver into said device.
30. A method of therapeutically treating a disorder in the oral
cavity, comprising: introducing a stick or pin having releasably
attached thereto a device according to claim 1 into the oral cavity
of a patient; and releasing the device in said oral cavity from the
stick or pin, thereby contacting an area of treatment in the oral
cavity, such that a therapeutic dose of nitric oxide is eluted from
said nitric oxide eluting polymer towards said area.
31. The method according to claim 30, wherein said area of
treatment is an infected area or an area where infection is to be
prevented.
32. The method according to claim 30, wherein said treatment area
is a post-operative dental surgery area.
33. The method according to claim 30, wherein said treatment area
is a tumor area.
34. The method according to claim 30, wherein said treatment area
is an area having paradontosis.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of PCT/EP2006/050888,
filed Feb. 13, 2006, which claims priority to European Patent
Application No. 05002937.0, filed Feb. 11, 2005; and U.S.
Provisional Application No. 60/652,758, filed Feb. 14, 2005. The
entire content of these applications is incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention pertains in general to the field of
therapeutical treatment of disorders in the oral cavity. More
particularly the invention relates to a device and method of
treatment of disorders in the oral cavity and a process for
manufacturing said device, involving Nitric Oxide (NO).
[0004] 2. Description of the Related Art
[0005] Infections by bacteria, viruses, fungi or yeasts are the
underlying cause of many complications during wound care. A wide
range of treatments has been developed to control such disorders,
including physical and chemical methods and antimicrobial agents of
a wide variety of antimicrobial agents. Despite the widespread use
of these approaches, it is generally recognized that our ability to
halt the invasion, persistence and spread of microbial infections
remain limited.
[0006] Treatment of disorders in the oral cavity, such as
paradontosis, is especially difficult, since the mucous membrane in
the oral cavity is exposed to a variety of substances from the
external (outside of the body) environment. Up to now the only
reliable treatment of infections in the oral cavity appears to be
the use of antibiotics. Treatment with antibiotics has certain
disadvantages, such as that the bacteria develops tolerance and
resistance to the antibiotics over time, and thus become difficult
to eradicate.
[0007] It is known that nitric oxide (NO) provides an alternative
to conventional therapies, such as antibiotics. Nitric oxide is a
highly reactive molecule that is involved in many cell functions.
In fact, nitric oxide plays a crucial role in the immune system and
is utilized as an effector molecule by macrophages to protect
itself against a number of pathogens, such as fungi, viruses,
bacteria etc., and general microbial invasion. This improvement of
healing is partly caused by NO inhibiting the activation or
aggregation of blood platelets, and also by NO causing a reduction
of inflammatory processes at the site of an implant. Furthermore,
NO has a vasodilating effect, which also affects, and promotes, the
healing process.
[0008] NO is also known to have an anti-pathogenic, especially an
anti-viral, effect, an anti-sacral effect, and furthermore NO has
an anti-cancerous effect, as it is cytotoxic and cytostatic in
therapeutic concentrations, i.e. it has among other effects
tumoricidal and bacteriocidal effects. NO has for instance
cytotoxic effects on human hematological malignant cells from
patients with leukemia or lymphoma, whereby NO may be used as a
chemotherapeutic agent for treating such hematological disorders,
even when the cells have become resistant to conventional
anti-cancer drugs.
[0009] However, due to the short half-life of NO, it has hitherto
been very hard to treat viral, bacteria, virus, fungi or yeast
infections with NO. This is because NO is actually toxic and has
negative effects when applied in too large amounts to the body. NO
is actually also a vasodilator, and too large amounts of NO
introduced into the body will cause a complete collapse of the
circulatory system. On the other hand, NO has a very short
half-life of fractions of a second up to a few seconds, once it is
released. Hence, administration limitations due to short half-life
and toxicity of NO have been limiting factors in the use of NO in
the field of anti-pathogenic and anti-cancerous treatment so
far.
[0010] In recent years research has been directed to polymers with
the capability of releasing nitrogen oxide when getting in contact
with water. Such polymers are for example polyalkyleneimines, such
as L-PEI (Linear PolyEthyleneImine) and B-PEI (Branched
PolyEthyleneImine), which polymers have the advantage of being
biocompatible.
[0011] US 2004/265244 discloses a composition and a method directed
to antimicrobial release of NO, in order to prevent gingival and
other mucosal diseases. The elution of NO from the device in US
2004/265244 is initiated by light activation of a
nitosyl-containing organometallic compound. Hence, the activation
process of US 2004/265244 is complicated. Furthermore, nothing is
mentioned in US 2004/265244 about regulating the release of nitric
oxide from the device.
[0012] U.S. Pat. No. 5,958,427 describes NO-donor compounds and
pharmaceutical compositions containing such NO-donor compounds, for
delivering NO to the apical surface of a mucosa. Nothing is
mentioned in U.S. Pat. No. 5,958,427 about regulating the release
of nitric oxide from the device.
[0013] EP 1 300 424 discloses extremely hydrophobic NO releasing
polymers. These polymers are extensively cross-linked
polyamine-derivatized divinylbenzene diazeniumdiolates. Since the
polymer according to EP 1 300 424 is extremely hydrophobic, it is
very unlikely that a sufficient elution on nitric oxide may be
obtained in the oral cavity. The mentioning of polyethylenimine,
page 9, line 35, is only in respect of excipient polymers to be
included in blends and copolymers. Nothing is mentioned in EP 1 300
424 about regulating the release of nitric oxide from the
device.
[0014] U.S. Pat. No. 5,691,423 discloses a polymeric, and
pharmaceutical, composition capable of releasing NO, said polymeric
composition comprising a polysaccharide including a NO releasing
N.sub.2O.sub.2.sup.- functional group bound to the polymer. Nothing
is mentioned in U.S. Pat. No. 5,691,423 about regulating the
release of nitric oxide from the device.
[0015] U.S. Pat. No. 6,737,447 discloses a coating for medical
devices, which coating provides NO delivery by using nanofibers of
L-PEI. U.S. Pat. No. 6,737,447 points out, and stresses, that the
coating is insoluble in water. This can only be interpreted as the
release of NO is initiated by something else than water.
Furthermore, nothing is mentioned in U.S. Pat. No. 6,737,447 about
regulating the release of nitric oxide from the device.
[0016] Other example for NO eluting polymers are given in U.S. Pat.
No. 5,770,645, wherein polymers derivatized with at least one
--NO.sub.X group per 1200 atomic mass unit of the polymer are
disclosed, X being one or two. One example is an S-nitrosylated
polymer and is prepared by reacting a polythiolated polymer with a
nitrosylating agent under conditions suitable for nitrosylating
free thiol groups.
[0017] Akron University has developed NO-eluting L-PEI molecule
that can be nano-spun onto the surface of medical devices such as
implanted grafts, showing significant improvement of the healing
process and reduced inflammation when implanting such devices.
According to U.S. Pat. No. 6,737,447, a coating for medical devices
provides nitric oxide delivery using nanofibers of linear
poly(ethylenimine)-diazeniumdiolate. Linear
poly(ethylenimine)diazeniumdiolate releases nitric oxide (NO) in a
controlled manner to tissues and organs to aid the healing process
and to prevent injury to tissues at risk of injury. Electrospun
nanofibers of linear poly(ethylenimine) diazeniumdiolate deliver
therapeutic levels of NO to the tissues surrounding a medical
device while minimizing the alteration of the properties of the
device. A nanofiber coating, because of the small size and large
surface area per unit mass of the nanofibers, provides a much
larger surface area per unit mass while minimizing changes in other
properties of the device.
[0018] However, the disclosure is both silent concerning an
improvement of present technology in respect of treatment of
disorders in the oral cavity, and the anti pathogenic potential of
nitric oxide, and how such treatment could be regulated.
[0019] Hence, an improved, and more advantageous, device for the
treatment and/or prevention of infection, caused by bacteria,
viruses, fungi or yeast or herpes is desired. It is also desired
that said device does not develop bacterial resistance, increases
circulation, and acts as a healing promoter. It is further desired
that the treatment could be regulated. It would be advantageous, in
particular, to provide a device allowing for target treatment of
both osteosynthetic and soft tissue healing post dental implant.
Prevention and treatment of paradontosis or other infected wounds
and cancer, and increased circulation, in the oral cavity, by means
of such a device, would be advantageous.
SUMMARY OF THE INVENTION
[0020] Accordingly, the present invention preferably seeks to
mitigate, alleviate or eliminate one or more of the
above-identified deficiencies in the art and disadvantages singly
or in any combination and solves, among others, the problems
mentioned above, by providing a device according to the appended
patent claims.
[0021] According to one aspect of the invention, a device is
provided that allows for target treatment of infections or wounds
in the oral cavity. The device comprises a nitric oxide (NO)
eluting polymer arranged to contact the infected area in the oral
cavity, such that a therapeutic dose of nitric oxide is eluted from
said nitric oxide eluting polymer to said area.
[0022] According to another aspect of the invention, a
manufacturing process for such a device is provided, wherein the
process is a process for forming a device that allows for target
treatment of infections or wounds in the oral cavity. The process
comprises selecting a plurality of nitric oxide eluting polymeric
fibers, and deploying said nitric oxide eluting fibers in a patch
or pad to be comprised in said device.
[0023] The present invention has at least the advantage over the
prior art that it provides target exposure of an infected or
wounded area to NO, whereby a very effective anti-viral,
anti-bacterial, anti-fungi and/or anti-cancer therapy is
achievable.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] These and other aspects, features and advantages of which
the invention is capable of will be apparent and elucidated from
the following description of embodiments of the present invention,
reference being made to the accompanying drawings, in which
[0025] FIG. 1 is a schematic illustration of a sponge according to
the invention,
[0026] FIG. 2 is a schematic illustration of a patch or pad
according to the invention,
[0027] FIG. 3 is a schematic illustration of another patch or pad
according to the invention, with NO-elution in one direction
only,
[0028] FIG. 4 is a schematic illustration of a condom/sheath
according to the invention,
[0029] FIG. 5 is a schematic illustration of nanoparticles, or
microspheres, according to the invention,
[0030] FIG. 6 is a schematic illustration of a mouth wash according
to the invention, and
[0031] FIG. 7 is an illustration of two elution profiles for two
different mixtures of nitric oxide eluting polymer and carrier
material.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0032] The following description focuses on an embodiment of the
present invention applicable to a device, in the form of a pad or
patch, which allows for target treatment of infections or wounds in
the oral cavity, such as paradontosis, herpes etc. However, also
alternative embodiments are described.
[0033] With regard to nitric oxide (nitrogen monoxide, NO), its
physiological and pharmacological roles have attracted much
attention and thus have been studied. NO is synthesized from
arginine as the substrate by nitric oxide synthase (NOS). NOS is
classified into a constitutive enzyme, cNOS, which is present even
in the normal state of a living body and an inducible enzyme, iNOS,
which is produced in a large amount in response to a certain
stimulus. It is known that, as compared with the concentration of
NO produced by cNOS, the concentration of NO produced by iNOS is 2
to 3 orders higher, and that iNOS produces an extremely large
amount of NO.
[0034] In the case of the generation of a large amount of NO as in
the case of the production by iNOS, it is known that NO reacts with
active oxygen to attack exogenous microorganisms and cancer cells,
but also to cause inflammation and tissue injury. On the other
hand, in the case of the generation of a small amount of NO as in
the case of the production by cNOS, it is considered that NO takes
charge of various protective actions for a living body through
cyclic GMP (cGMP), such as vasodilator action, improvement of the
blood circulation, antiplatelet-aggregating action, antibacterial
action, anticancer action, acceleration of the absorption at the
digestive tract, renal function regulation, neurotransmitting
action, erection (reproduction), learning, appetite, and the like.
Heretofore, inhibitors of the enzymatic activity of NOS have been
examined for the purpose of preventing inflammation and tissue
injury, which are considered to be attributable to NO generated in
a large amount in a living body. However, the promotion of the
enzymatic activity (or expressed amount) of NOS (in particular,
cNOS) has not been examined for the purpose of exhibiting various
protective actions for a living body by promoting the enzymatic
activity of NOS and producing NO appropriately.
[0035] In recent years research has been directed to polymers with
the capability of releasing nitrogen oxide when getting in contact
with water. Such polymers are for example polyalkyleneimines, such
as L-PEI (Linear PolyEthyleneImine) and B-PEI (Branched
PolyEthyleneImine), which polymers have the advantage of being
biocompatible.
[0036] The polymers may be manufactured by electro spinning, gas
spinning, air spinning, wet spinning, dry spinning, melt spinning,
and gel spinning. Electro spinning is a process by which a
suspended polymer is charged. At a characteristic voltage a fine
jet of polymer releases from the surface in response to the tensile
forces generated by interaction by an applied electric field with
the electrical charge carried by the jet. This process produces a
bundle of polymer fibers, such as nanofibers. This jet of polymer
fibers may be directed to a surface to be treated.
[0037] In other embodiments the polymers may be manufactured by air
spinning, wet spinning, dry spinning, melt spinning, or gel
spinning.
[0038] Furthermore, U.S. Pat. No. 6,382,526, U.S. Pat. No.
6,520,425, and U.S. Pat. No. 6,695,992 disclose alternative
processes and apparatuses for the production of such polymeric
fibers. These techniques are generally based on gas stream
spinning, also known within the fiber forming industry as air
spinning, of liquids and/or solutions capable of forming
fibers.
[0039] In an embodiment of the invention, according to FIG. 1, the
device 10 is in form of a nano-spun, NO-eluting sponge or fiber
coated sponge or sponge-like device, such as a sponge or a cotton
ball or pillow. This NO-eluting sponge may be placed between the
lip and teeth to increase circulation and prevent infection. When
the nano-spun, NO-eluting sponge according to the present invention
gets in contact with the moisture in the oral cavity the NO-eluting
sponge starts to release NO to the area to be treated. This
nano-spun NO-eluting sponge is preferably comprised of nano-spun
fibers of a polymer that elutes NO. Such polymers are for example
polyalkyleneimines, such as L-PEI (Linear PolyEthyleneImine) or
B-PEI (Branched PolyEthyleneImine), which polymers have the
advantage of being biodegradable to natural products or
biocompatible with the latter.
[0040] This sponge has the advantage that it is easily activated.
Furthermore, the NO is applied locally, without influencing other
parts of the body, due to the short half-life of the NO eluted from
the NO eluting polymer material. Thus, implications concerning the
vascular system are kept very local and low, while at the same time
the effect of NO is optimally exploited.
[0041] In another embodiment the sponge according to an embodiment
of the present invention is applied to the oral cavity with the aid
of a stick or pin at the area to be treated. This area may be
anywhere in the oral cavity, such as between the gum and the teeth,
between the teeth, in a dental pocket, etc. More specifically, the
sponge is for instance releasably attached to the stick, preferably
to an end of the stick. The end is then introduced into the oral
cavity together with the sponge, where it is released from the
stick, e.g. by counter holding the sponge with two fingers and
drawing back the stick. The stick is thus removed from the oral
cavity, leaving the sponge behind in the oral cavity for treatment
therein.
[0042] Akron University has developed NO-eluting L-PEI molecule
that can be nano-spun onto the surface of medical devices
permanently implantable into the human body, showing significant
improvement of the healing process and reduced inflammation when
implanting such devices. According to U.S. Pat. No. 6,737,447, a
coating for medical devices provides nitric oxide delivery using
nanofibers of linear poly(ethylenimine)-diazeniumdiolate. Linear
poly(ethylenimine)diazeniumdiolate releases nitric oxide (NO) in a
controlled manner.
[0043] However, the meaning of "controlled" in the context of U.S.
Pat. No. 6,737,447 is only directed to the fact that nitric oxide
is eluted from the coating during a period of time, i.e. that the
nitric oxide is not eluted all in once. Therefore, the
interpretation of "controlled" in respect of U.S. Pat. No.
6,737,447 is different from the meaning of "regulating" in the
present invention. "Regulate or control", according to the present
invention is intended to be interpreted as the possibility to vary
the elution of nitric oxide to thereby achieve different elution
profiles.
[0044] A polymer comprising an O-nitrosylated group is also a
possible nitric oxide eluting polymer. Thus, in one embodiment of
the present invention, the nitric oxide eluting polymer comprises
diazeniumdiolate groups, S-nitrosylated and O-nitrosylated groups,
or any combinations thereof.
[0045] In still another embodiment of the present invention said
nitric oxide eluting polymer is a
poly(alkyleneimine)diazeniumdiolate, such as L-PEI-NO (linear
poly(ethyleneimine)diazeniumdiolate), where said nitric oxide
eluting polymer is loaded with nitric oxide through the
diazeniumdiolate groups and arranged to release nitric oxide at a
treatment site.
[0046] Some other examples of a suitable nitric oxide eluting
polymer are selected from the group comprising amino cellulose,
amino dextrans, chitosan, aminated chitosan, polyethyleneimine,
PEI-cellulose, polypropyleneimine, polybutyleneimine, polyurethane,
poly(buthanediol spermate), poly(iminocarbonate), polypeptide,
Carboxy Methyl Cellulose (CMC), polystyrene, poly(vinyl chloride),
and polydimethylsiloxane, or any combinations of these, and these
mentioned polymers grafted to an inert backbone, such as a
polysaccharide backbone or cellulosic backbone.
[0047] In still another embodiment of the present invention the
nitric oxide eluting polymer may be a O-derivatized NONOate. This
kind of polymer often needs an enzymatic reaction to release nitric
oxide.
[0048] Other ways of describing polymers, which may be suitable as
nitric oxide eluting polymer, is polymers comprising secondary
amine groups (.dbd.N--H), such as L-PEI, or have a secondary amine
(.dbd.N--H) as a pendant, such as aminocellulose.
[0049] It is preferable that the nano-spun fibers in the NO-eluting
sponge according to the embodiment of present invention comprise
L-PEI. This embodiment of course permits the sponge to be placed in
another location in the oral cavity than between the lip and the
teeth. When placed on an area to be treated the device provides for
promotion of osteosynthetic and soft tissue healing, as well as
prevention and treatment of paradontosis, infections or wounds,
thanks to the effect of NO eluting from the sponge into the regions
to be treated. One of the advantages of electrospun or gas-jet spun
nanofibers is their large surface area per volume unit. For the
sponge this leads to a very effective treatment with a compact
device.
[0050] One field of application of the device is post dental
implant, e.g. accelerated healing thereof, or post-operative
infection control, which is simplified and made more effective and
convenient by the invention.
[0051] Other examples of NO eluting polymers are given in U.S. Pat.
No. 5,770,645, wherein polymers derivatized with at least one --NOX
group per 1200 atomic mass unit of the polymer are disclosed, X
being one or two. One example is an S-nitrosylated polymer and is
prepared by reacting a polythiolated polymer with a nitrosylating
agent under conditions suitable for nitrosylating free thiol
groups. Such polymers may also be used for other embodiments of the
devices according to the present invention. However, L-PEI is
preferred, as the NO is eluted without any secondary products that
could lead to undesired side effects as a result of treatment with
the devices described herein.
[0052] In another embodiment the device according to the present
invention is in the form of a pad or patch 20, according to FIG. 2.
The pad or patch is coated with or comprises at least partly, at
least on one side, nano-spun fibers, which according to embodiments
of the present invention comprise the materials mentioned above,
regarding the sponge. The nano-spun fibers elute NO in a
therapeutic dose as the nano-spun fibers that release NO, which is
eluted from the fibers without harmful secondary or waste products,
are activated for this purpose when they get in contact with the
moisture in the oral cavity. This embodiment has the advantage that
it is easily applicable, and removable, on, and from, the target
area. Furthermore, this pad or patch has the advantage that it is
easily activated. Furthermore, the NO is applied locally, without
influencing other parts of the body, due to the short half-life of
the NO eluted from the NO eluting polymer material. Alternatively,
if the oral cavity for some reason should be deprived of humidity,
the patch, and also other devices according to embodiments of the
invention, may be activated immediately prior to introduction or in
the cavity, e.g. by moisturizing them in a bath of water or by a
water sprayed onto the device.
[0053] The device according to this embodiment of the present
invention may in a further embodiment be soluble in the oral
cavity. When the device is subjected to the moisture in the oral
cavity, the device is disintegrated in its entirety, wherein the
time for dissolving the device is adapted to specific requirements,
as for instance therapeutic concentrations to be released over
time. This embodiment has the advantage that it is easily
applicable and does not have to be removed for replacement by
another device or after the therapeutic treatment with the device
is completed.
[0054] In another embodiment of the present invention the device or
system only allows NO-elution in one direction. In this kind of
embodiment one side of the device according to the invention has
low permeability, or substantially no permeability, to nitric
oxide. This may be accomplished by applying a material on one side
of the device according to the invention that is not permeable to
NO. Such materials may be chosen from the group comprising common
plastics, such as fluoropolymers, polyethylene, polypropylene,
polyacrylonitrile, polyurethane, polyvinylacetates,
polylacticacids, starch, cellulose, polyhydroxyalkanoates,
polyesters, polycaprolactone, polyvinylalcohol, polystyrene,
polyethers, polycarbonates, polyamides, polyolefins, poly(acrylic
acid), Carboxy Methyl Cellulose (CMC), protein based polymers,
gelatine, biodegradable polymers, cotton, and latex, or any
combinations of these. This embodiment is also easy to manufacture
as the NO eluting polymer, e.g. L-PEI (or nitric oxide eluting
polymer and carrier material, which will be explained in more
detail below) may be electro or gas-jet spun onto the surface of
the device according to the invention of e.g. the mentioned
plastics, latex, or cotton.
[0055] In still another embodiment the device is provided with one
membrane, which is permeable to nitric oxide, on a first side of
the device, and another membrane, which has low permeability or
substantially no permeability to nitric oxide, on a second side of
said device. This embodiment provides the possibility to direct the
elution to said first of the device, while the elution of nitric
oxide is substantially prevented from said second side. Thereby, a
greater amount of nitric oxide will reach the intended area to be
treated.
[0056] In another embodiment of the present invention the device
only allows NO-elution in one direction, according to FIG. 3. In
this kind of embodiment one side of the patch or pad 30 is
non-permeable to NO. This may be accomplished by applying a
material on one side of the patch or pad that is not permeable to
NO. Such materials may be chosen from the group comprising common
plastics, such as polyethylene, polypropylene, polyacrylonitrile,
polyurethane, polyvinylacetates, polylacticacids, starch,
cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone,
polyvinylalcohol, polystyrene, polyethers, polycarbonates,
polyamides, polyolefins, poly(acrylic acid), Carboxy Methyl
Cellulose (CMC), protein based polymers, gelatine, biodegradable
polymers, cotton, and latex, or any combinations of these. In this
way, the therapeutic effect of NO is easily directable to certain
regions in the oral cavity without interfering with other regions
therein.
[0057] A further embodiment of the invention is illustrated in FIG.
4, in which the device is shaped as a condom/sheath 40, which
either is made of an NO eluting polymer or coated with it, e.g. by
nano electro-spinning or gas-jet spinning. According to this
embodiment the condom/sheath may be mounted on a stick 41 for
easier application. The condom/sheath may be applied by inserting
the stick, with the condom/sheath according to the present
invention mounted thereon, adjacent to the area to be treated. Then
the stick may be extracted from the oral cavity. The condom/sheath
is left adjacent to the area to be treated. This area may be areas
such as in between the teeth, the tooth pocket, or any other area
in the oral cavity where the condom/sheath is applicable.
[0058] This condom/sheath may of course be in any suitable size,
such as a size suitable for inserting said condom/sheath between
the teeth or in a tooth pocket. The condom/sheath is then inserted
on the preferred area to be treated with the aid of a suitable
means, such as a stick or pin. This embodiment has the advantages
that it is easy to pin point the treatment area and it is easy to
apply.
[0059] In still another embodiment of the present invention
NO-eluting nanoparticles, or microspheres, may be formed from
NO-eluting polymers, according to FIG. 5. These nanoparticles, e.g.
in the form of microspheres may be integrated in a soluble film
that disintegrates e.g. in between the lip and the dental soft
tissue, in the dental pocket, or any other area in the oral cavity
where the device is applicable, in order to elute NO at the area of
interest when soluble film gets in contact with the moisture in the
oral cavity, or between the inside of the cheek and the gum, in one
direction or both.
[0060] In another embodiment of the present invention the
nanoparticles, or microspheres, of the polymers in the present
invention, may be encapsulated in a material that breaks upon the
stress from chewing or brushing the teeth. Then said nanoparticles,
or microspheres, may be integrated in chewing gum or toothpaste.
This kind of chewing gum or toothpaste may then be used to prevent
or treat disorders in the oral cavity, such as infections, cancer,
or paradontosis, or to promote osteosynthesis and soft tissue
healing post dental implant. The materials used to encapsulate
these nanoparticles, or microspheres, may be chosen from the group
comprising polyethylene, polypropylene, polyacrylonitrile,
polyurethane, polyvinylacetates, polylacticacids, starch,
cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone,
polyvinylalcohol, polystyrene, polyethers, polycarbonates,
polyamides, polyolefins, poly(acrylic acid), Carboxy Methyl
Cellulose (CMC), protein based polymers, gelatine, biodegradable
polymers, cotton, and latex, or any combinations of these. This
embodiment has the advantages that it is easy to apply, the
treatment effect covers the whole oral cavity, and it is easy to
manufacture.
[0061] In the context of the present invention the term
"encapsulating" is intended to be interpreted as fixating the
nitric oxide eluting polymer in a three dimensional matrix such as
a foam, a film, a nonwoven mat of nanofibers or fibers, other
materials with the capability to fixate the NO eluting polymer, or
enclosing the nitric oxide eluting polymer in any suitable
material.
[0062] In still another embodiment of the present invention the
nanoparticles, or microspheres, may combined with a suitable
mouthwash, such as chlorine dioxide (ClO.sub.2), according to FIG.
6. When the mouthwash is used in the oral cavity, the
nanoparticles, or microspheres, break and NO is released. Of
course, chlorine dioxide may be combined with all the embodiments
according to the present invention, such as the patch. This offers
the advantage of further promoting the anti-bacterial effect of
NO.
[0063] In yet another embodiment of the present invention the
NO-eluting device is acting as a booster for drug eluting patches,
e.g. pharmaceuticals, vitamins, nicotin, nitroglycerin etc. This
embodiment presents a device with the advantage of combining two
therapeutic treatments, of significant value, in one treatment. A
synergetic effect may be that NO that is eluted from the device has
a vasodilatory effect on the region where the device having the
combination compound actuates. Vasodilated tissue is more
susceptible to certain medications and thus more easily treated by
the medical preparations and still NO has in addition to that the
anti-inflammatory, anti-bacterial etc. effect. Hence, an unexpected
surprisingly effective treatment is provided.
[0064] In still another embodiment the nitric oxide eluting
polymer, such as powder, nanoparticles or microspheres, can be
incorporated in foam. The foam may have an open cell structure,
which facilitates the transport of the proton donor to the nitric
oxide eluting polymer. The foam can be of any suitable polymer such
as polyethylene, polypropylene, polyacrylonitrile, polyurethane,
polyvinylacetates, polylacticacids, starch, cellulose,
polyhydroxyalkanoates, polyesters, polycaprolactone,
polyvinylalcohol, polystyrene, polyethers, polycarbonates,
polyamides, polyolefins, poly(acrylic acid), Carboxy Methyl
Cellulose (CMC), protein based polymers, gelatine, biodegradable
polymers, cotton, and latex, or any combinations of these.
[0065] In another embodiment the device is in the form of a cream,
a gel or a combination of the two. This embodiment has the
advantage of being able to penetrate pockets and corners, e.g. in
the gum or skin for closer elution of NO on the area to be
treated.
[0066] In another embodiment the device is in the form of a cream,
a gel or a combination of the two. Since the nitric oxide eluting
polymer is activated by proton donors the nitric oxide eluting
polymer has to be separate from the proton donor until one wants to
initiate the elution of nitric oxide, i.e. use the device. One way
to accomplish this is to have a syringe with two separate
containers. In one container you have a proton donor-based gel and
in the other a non proton donor-based gel, comprising the nitric
oxide eluting polymer. Upon using the device the two gels are
squeezed from the syringe and mixed together, the proton donor in
the first gel comes in contact with the nitric oxide eluting
polymer in the second gel and the elution of nitric oxide
starts.
[0067] In still another embodiment of the present invention dental
implants, such as screws of titanium, and other biodegradable or
biocompatible plates, may be integrated with the fibers,
nanoparticles, or microspheres according to the present invention,
e.g. by coating the devices. A very convenient way for coating is
offered by electro-spinning or gas-jet spinning of NO eluting
polymers onto the surface of the devices. This embodiment decreases
the risk of infections during surgical procedures in the oral
cavity.
[0068] The device may include materials such as polyethylene,
polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates,
polylacticacids, starch, cellulose, polyhydroxyalkanoates,
polyesters, polycaprolactone, polyvinylalcohol, polystyrene,
polyethers, polycarbonates, polyamides, polyolefins, poly(acrylic
acid), Carboxy Methyl Cellulose (CMC), protein based polymers,
gelatine, biodegradable polymers, cotton, and latex, or any
combinations of these. The NO-eluting polymer may be integrated in,
spun together with, or spun on top of, any of these materials in
all of the embodiments of the present invention.
[0069] Three important factors in controlling and regulating the
elution of nitric oxide from a nitric oxide eluting polymer are how
quickly a proton donor comes in contact with the nitric oxide
releasing polymer, such as a diazoliumdiolate group, the acidity of
the environment surrounding the nitric oxide eluting polymer, and
the temperature of the environment surrounding the nitric oxide
releasing polymer (higher temperature promotes elution of nitric
oxide).
[0070] In one embodiment of the present invention a nitric oxide
eluting polymer, such as L-PEI-NO, is mixed with a carrier polymer
to slow down or prolong the elution of nitric oxide. Also, in
another embodiment, the nitric oxide eluting polymer may be mixed
with more than one carrier polymer, whereby be elution or release
may be tailor made to fit specific needs. Such a need may for
example be a low elution during a first period of time, when the
environment of the nitric oxide eluting polymer is hydrophobic, and
a faster elution during a second period of time, when the
environment of the nitric oxide eluting polymer has been altered to
be more hydrophilic. This may for example be accomplished by using
biodegradable polymers, whereby a low elution during a first period
of time is obtained, after which, when the hydrophobic polymer has
been dissolved, the hydrophilic polymer provides a higher elution
of nitric oxide. Thus, a more hydrophobic carrier polymer will give
a slower elution of nitric oxide, since the activating proton
donor, such as water or body fluid, will penetrate the carrier
polymer slower. On the other hand, a hydrophilic polymer acts the
opposite way. One example of an hydrophilic polymer is polyethylene
oxide, and one example of an hydrophobic polymer is polystyrene.
These carrier polymers may be mixed with the nitric oxide eluting
polymer and then electrospun to suitable fibers. The skilled person
in the art knows which other polymers may be used for similar
purposes. FIG. 7 illustrates two elution profiles (NO concentration
vs. time) for two different polymer mixtures; a nitric oxide
eluting polymer mixed with a hydrophilic carrier polymer in an
acidic environment (A), and a nitric oxide eluting polymer mixed
with a hydrophobic carrier polymer in a neutral environment
(B).
[0071] In one embodiment this carrier polymer is substituted by
another material with hydrophobic or hydrophilic properties.
Therefore, the term "carrier material" in the present context
should be interpreted to include carrier polymers and other
materials with hydrophilic or hydrophobic properties.
[0072] In another embodiment of the present invention the elution
of nitric oxide from a nitric oxide eluting polymer, such as
L-PEI-NO, is influenced by the presence of protons. This means that
a more acidic environment provides a quicker elution of nitric
oxide. By activating the nitric oxide eluting polymer, or mixture
of nitric oxide eluting polymer and carrier material, with an
acidic fluid, such as an ascorbic acid solution, the elution of
nitric oxide may be accelerated.
[0073] The carrier polymers and carrier materials mentioned above
may affect other characteristics than the regulation of nitric
oxide elution. An example of such characteristic is mechanical
strength.
[0074] In respect of the carrier polymers or carrier materials, the
NO-eluting polymer may be integrated in, spun together with, or
spun on top of, any of these materials in all of the embodiments of
the present invention. This spinning includes electrospinning, air
spinning, wet spinning, dry spinning, melt spinning, gel spinning.
In this way, one may manufacture fibers of a polymer mixture,
comprising a nitric oxide eluting polymer and a carrier polymer, or
a carrier material, with predefined nitric oxide eluting
characteristics. These characteristics may be tailor made for
different elution profiles in different applications.
[0075] The device elutes nitric oxide (NO) from said eluting
polymer in a therapeutic dose, such as between 0.001 to 5000 ppm,
such as 0.01 to 3000 ppm, such as 0.1 to 1000 ppm, such as 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,
39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,
56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,
73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,
90 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 ppm. The
concentration may vary widely depending on where the concentration
is measured. If the concentration is measured close to the actual
NO eluting polymer the concentration may be as high as thousands of
ppm, while the concentration inside the tissue in this case often
is considerably lower, such as between 1 to 1000 ppm.
[0076] In the embodiments of the present invention it may be
suitable to control or regulate the time span of NO release from
the device according to the invention. This may be accomplished by
integrating other polymers or materials in said device. These
polymers or materials may be chosen from any suitable material or
polymer, such as polyethylene, polypropylene, polyacrylonitrile,
polyurethane, polyvinylacetates, polylacticacids, starch,
cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone,
polyvinylalcohol, polystyrene, polyethers, polycarbonates,
polyamides, polyolefins, poly(acrylic acid), Carboxy Methyl
Cellulose (CMC), protein based polymers, gelatine, biodegradable
polymers, cotton, and latex, or any combinations of these.
[0077] The sizes of the devices according to the present invention
may of course vary widely within in the parameters conveniently
used in the oral cavity, but the size is typically 7 to 15
mm.times.20 to 40 mm, preferably 9 to 13 mm.times.25 to 35 mm, such
as 10 mm.times.30 mm.
[0078] The NO-eluting polymers in the devices according to the
present invention may be combined with silver, such as
hydroactivated silver. The integration of silver in the devices
according to the present invention gives the healing process an
extra boost. Preferably the silver is releasable from the devices
in the form of silver ions. The integration of silver in the device
may present several advantages. One example of such an advantage is
that the silver may keep the device in itself free from bacteria or
viruses, while the nitric oxide eluting polymer elutes the
therapeutic dosage of nitric oxide to the target site.
[0079] The nitric oxide eluting polymer may comprise a secondary
amine, either in the backbone or as a pendant, as described
previously. This will make a good nitric oxide eluting polymer. The
secondary amine should have a strong negative charge to be easy to
load with nitric oxide. If there is a ligand close to the secondary
amine, such as on a neighbor atom, such as a carbon atom, to the
nitrogen atom, with higher electronegativity than nitrogen (N), it
is very difficult to load the polymer with nitric oxide. On the
other hand, if there is a electropositive ligand close to the
secondary amine, such as on a neighbor atom, such as a carbon atom,
to the nitrogen atom, the electronegativity of the amine will
increase and thereby increase the possibility to load the nitric
oxide elution polymer with nitric oxide.
[0080] In an embodiment of the present invention the nitric oxide
polymer may be stabilized with a salt. Since the nitric oxide
eluting group, such as a diazeniumdiolate group, usually is
negative, a positive counter ion, such as a cation, may be used to
stabilize the nitric oxide eluting group. This cation may for
example be selected from the group comprising any cation from group
1 or group 2 in the periodic table, such as Na.sup.+, K.sup.+,
Li.sup.+, Be.sup.2+, Ca.sup.2+, Mg.sup.2+, Ba.sup.2+, and/or
Sr.sup.2+. Different salts of the same nitric oxide eluting polymer
have different properties. In this way a suitable salt (or cation)
may be selected for different purposes. Examples of cationic
stabilized polymers are L-PEI-NO-Na, i.e. L-PEI diazeniumdiolate
stabilized with sodium, and L-PEI-NO-Ca, i.e. L-PEI
diazeniumdiolate stabilized with calcium.
[0081] Another embodiment of the present invention comprises mixing
the nitric oxide eluting polymer, or a mixture of the nitric oxide
eluting polymer and a carrier material, with an absorbent agent.
This embodiment provides the advantage of an accelerated elution of
nitric oxide since the polymer, or polymer mixture, via the
absorbent agent, may take up the activating fluid, such as water or
body fluid, much faster. In one example 80% (w/w) absorbent agent
is mixed with the nitric oxide eluting polymer, or mixture of
nitric oxide eluting polymer and carrier material, and in another
embodiment 10 to 50% (w/w) absorbent agent is mixed with the nitric
oxide eluting polymer, or mixture of nitric oxide eluting polymer
and carrier material.
[0082] Since the elution of nitric oxide is activated by a proton
donor, such as the water in the oral cavity, it may be an advantage
to keep the nitric oxide eluting polymer, or mixture of nitric
oxide eluting polymer and carrier material, in contact with said
proton donor. If an indication requires an elution of nitric oxide
during a prolonged period of time, a system is advantageous, which
presents the possibility to keep the proton donor in contact with
the nitric oxide eluting polymer, or mixture of nitric oxide
eluting polymer and carrier material. Therefore, in still another
embodiment of the present invention, the elution of nitric oxide
may be regulated by adding an absorbent agent. The absorbent agent
absorbs the proton donor, such as water, and keeps the proton donor
in close contact with the nitric oxide eluting polymer during
prolonged periods of time. Said absorbent agent may be selected
from the group comprising polyacrylates, polyethylene oxide,
carboxymethylcellulose, and microcrystalline cellulose, cotton, and
starch. This absorbent agent may also be used as a filling agent.
In this case said filling agent may give the nitric oxide eluting
polymer, or mixture of said nitric oxide eluting polymer and a
carrier material, a desired texture.
[0083] The device may be manufactured by, for example electro
spinning of L-PEI. L-PEI is the charged at a characteristic
voltage, and a fine jet of L-PEI releases as a bundle of L-PEI
polymer fibers. This jet of polymer fibers may be directed to a
surface to be treated. The surface to be treated may for example be
any suitable material in respect of a device. The electro spun
fibers of L-PEI then attach on said material and form a
coating/layer of L-PEI on the device according to the
invention.
[0084] It is of course possible to electro spin the other
NO-eluting polymers, according to above, on the device according to
the invention while still being inside the scope of the present
invention.
[0085] Other manufacturing methods, such as wet spinning, dry
spinning, melt spinning, and gel spinning, are also within the
scope of the present invention.
[0086] In one embodiment the NO-eluting polymers according to the
present invention are electro spun in such way that pure NO-eluting
polymer fibers may be obtained.
[0087] Gas stream spinning, air spinning, wet spinning, dry
spinning, melt spinning, and gel spinning, of said NO-eluting
polymers onto the device is also within the scope of the present
invention.
[0088] The manufacturing process according to the present invention
presents the advantages of large contact surface of the NO-eluting
polymer fibers with the area to be treated, effective use of
NO-eluting polymer, and a cost effective way of producing the
device.
[0089] The device according to the invention may of course be used
in any post surgery treatment to prevent, treat, and/or alleviate
any kind of infection or inflammation. Especially to prevent
disorders post surgery in the oral cavity. The effects of NO are
provided in a convenient way by the device of the invention. Such
effects are for instance, as mentioned above, anti-inflammatory,
anti-pathogenic, especially anti-viral and anti-bacterial.
Furthermore the anti-cancerous effect of NO may be taken advantage
of, e.g. for bone cancer treatment of the jaw.
[0090] Hereinafter some potential uses of the present invention are
described:
[0091] A method of therapeutically treating disorders in the oral
cavity, comprising introducing a stick or pin having releasably
attached thereto a device according to the present invention into
the oral cavity of a patient, releasing the device, in the oral
cavity of the patient, from the stick or pin, thereby contacting an
area of treatment in the oral cavity, such that a therapeutic dose
of nitric oxide is eluted from said nitric oxide eluting polymer to
said area.
[0092] The method according to the above, wherein said area of
treatment is an infected area in the oral cavity or an area where
infection is to be prevented.
[0093] The method according to the above, wherein said treatment
area is a post-operative dental surgery area.
[0094] The method according to the above, wherein said treatment
area is a tumor area in the oral cavity.
[0095] Use of nitric oxide (NO) in a therapeutic dose for the
treatment of disorders in the oral cavity, wherein said use for
instance is the treatment or prevention of paradontosis.
[0096] The invention can be implemented in any suitable form. The
elements and components of the embodiments according to the
invention may be physically, functionally, and logically
implemented in any suitable way. Indeed, the functionality may be
implemented in a single unit, in a plurality of units, or as part
of other functional units.
[0097] Although the present invention has been described above with
reference to specific embodiments, it is not intended to be limited
to the specific form set forth herein. Rather, the invention is
limited only by the accompanying claims and, other embodiments than
the specific above are equally possible within the scope of these
appended claims.
[0098] In the claims, the term "comprises/comprising" does not
exclude the presence of other elements or steps. Furthermore,
although individually listed, a plurality of means, elements or
method steps may be implemented. Additionally, although individual
features may be included in different claims, these may possibly
advantageously be combined, and the inclusion in different claims
does not imply that a combination of features is not feasible
and/or advantageous. In addition, singular references do not
exclude a plurality. The terms "a", "an", "first", "second" etc do
not preclude a plurality. Reference signs in the claims are
provided merely as a clarifying example and shall not be construed
as limiting the scope of the claims in any way.
* * * * *